Incidence and determinants of adverse events in individuals with HIV commencing Dolutegravir-based antiretroviral therapy in mainland Tanzania

Tanzania adopted a Dolutegravir (DTG)-based regimen as first-line treatment in 2019 following the World Health Organization recommendation. Data on the DTG safety profile from sub-Saharan Africa including Tanzania are limited. We investigated the incidence of DTG-related adverse events (AEs) and associated factors among people living with HIV (PLHIV) initiated on a DTG regimen. A prospective cohort study was conducted from 25 Care and Treatment Clinics in mainland Tanzania. PLHIV aged 12 years and above who were initiated on a DTG-based regimen were actively followed up for three months. The Cox regression model was used to determine the predictors of occurrence of AEs over time. A p-value of 0.05 was considered statistically significant. From January 2020 to June 2022, a cohort of 935 participants who were both newly diagnosed and ART-experienced who transitioned to a DTG-based regimen was enrolled. Out of 935 participants, 59 (6.3%) reported a total of 62 AEs. The most frequently experienced AE was skin itching and rashes (15/62; 24.2%). DTG-associated neuropsychiatric AEs were less common and included headache (6 [9.6%]) and sleep disturbances (3 [4.8%]). The overall incidence of occurrence of the first AEs was 96.7 per 1000 person-months [95% C.I: 74.4–125.7] with the highest incidence observed among the elderly (≥ 60 years). Individuals on WHO HIV Clinical Stage 2 had a 2.7 significantly higher risk of developing AEs (adjusted hazard ratio = 2.73, 95% CI = 1.46–5.12, p = 0.017). We report a low incidence of grade I (mild) and grade II (moderate) DTG-associated AEs suggesting that the regimen is generally safe in the population. Continued monitoring of DTG safety in the population is recommended.

adverse reactions, which may lead to attrition of patients from care [4][5][6] .The incidence of ARTs-related adverse drug reactions (ADR) has been reported to range from 11 to 35.9% in both developed and developing countries 7 .
In 2014, the Joint United Nations Programme launched the 90-90-90 AIDS program which was later updated to 95-95-95 in 2020, targeting to diagnose 95% of all HIV-positive individuals, provide ART for 95% of those diagnosed and achieve viral suppression for 95% of those treated by 2030 8 .As of 2021, Tanzania has made significant progress towards achieving the 95-95-95 targets as indicated by the increased ART coverage to 86% 2, 9 .Nevertheless, the achievement of these targets is affected by several factors including drug resistance and ADRs related to some ART drugs.
DTG is a second-generation integrase-strand transfer inhibitor (INSTI) with higher efficacy, excellent tolerability, infrequent drug-drug interactions and mild adverse events 2, 10 .Due to its safety profile and fewer chances of developing resistance, the World Health Organization (WHO) recommended a DTG-based regimen to be the first line of ART to stimulate progress towards achieving the 95-95-95 targets 11,12 .Tanzania adopted a DTG-based regimen as a first and second-line regimen in 2019.
Studies done in real-world settings reported DTG-associated neuropsychiatric adverse reactions and increased risk of neural tube defects among infants [13][14][15][16][17][18] .These AEs may negatively impact ART adherence leading to discontinuation, therapeutic failure, and viral resistance interrupting the achievement of 95-95-95 AIDS targets [19][20][21] .Data on the DTG safety profile from sub-Saharan African countries are limited 7,9,22 .A large study conducted in six Eastern-southern African countries including Tanzania, reported that a DTG based regimen was safe with mild AEs among children and adolescents 23 .Similarly, mild to moderate AEs were reported among children and adolescents attending CTC in the Mbeya region, mainland Tanzania 24 .While adults comprise the majority of PLHIV, data on DTG safety profiles among adults from Tanzania are not available to the best of our knowledge.The present study reports the incidence of AEs and risk factors among adolescents and adults PLHIV initiated on a DTG based regimen from 11 regions of mainland Tanzania.

Baseline characteristics of study participants
Figure 1 indicates the number of individuals recruited from each administrative zone and the corresponding total number of those followed up to 90 days.Among 1500 individuals recruited, 250 participants were excluded at enrollment due to age (< 12 years) or serious illness that needed hospitalization.From January 2020 to June 2022, a total of 935 participants were followed up for 90 days (Fig. 1).
The majority of participants were females (591) (63.2%).More than eighty per cent were aged between 25 and 59 years (763/935; 81.6%), with the median age (IQR) of the study population being 35 (28, 44) years.At baseline, the majority of participants had a body weight of more than 40 kg (882/935; 94.3%), and about twothirds of them were categorized as WHO HIV clinical stage I (628/935; 67.2%).Participants with a CD4 cell count of ≥ 500 cells/mm 3 accounted for the majority (436/935; 46.6%).Table 1 presents the baseline characteristics of the study population.

Incidence rates of adverse events
A total of 56 AEs were analyzed during 578.97 person-months of follow-up.The overall incidence of occurrence of the first AEs was 96.7 per 1000 person-months (pm) [95% C.I 74.4-125.7]. Figure 4 shows the Kaplan-Meier plot for the time to events.The median time to the first AE with a 95% confidence interval was 87.9 (47.4 to 128.4) days (Fig. 4).
The highest incidence was observed among the elderly aged 60 years and above, individuals in WHO HIV Clinical Stage 2, individuals who were widowed/separated and individuals with a secondary level of education (Table 2).

Risk factors for incidence rates of reported AEs
In the univariable analysis, the WHO HIV clinical stage was the significant predictor of reported AEs.After adjusting for potential confounders, WHO HIV clinical stage II, was the only independent risk factor for developing AEs within 90 days after initiating TLD (adjusted hazard ratio (aHR) = 2.73, 95% CI = 1.46-5.12)(Table 3).

Discussion
The major findings of this prospective study include a relatively low incidence of reported AEs suggesting that a DTG-based regimen is generally safe in the population; geriatrics and participants with WHO HIV clinical stage 2 were more likely to report AEs.
The proportion of participants who experienced at least one AE in this study was 6.3%.Our finding is relatively lower compared to that reported in other studies conducted among patients who also initiated DTG-based regimens in Brazil (10%), Kenya (18%) 25 and Uganda (33%) 26 .Our study had a relatively larger sample size than these previous studies which might partly explain the observed differences, albeit other predisposing factors might also explain.The reported AEs were mild and included skin itching and rashes, nausea and vomiting, tiredness, diarrhoea, fever and stomach pain corroborating with several other studies 26 .Neuropsychiatric AEs were reported as one of the reasons for discontinuation of DTG-based regimens in previous studies 12,27 .However, in our present study, few individuals reported neuropsychiatric AEs which were mild and tolerable including headache, sleep disturbances and dizziness suggesting that AEs associated with treatment discontinuation may be less likely.The reason for the observed differences could be due to the design of the studies, or other predisposing factors across the different populations.Similar to our study, a previous study done in Switzerland reported a low proportion of neuropsychiatric AEs 28 .
DTG is also known to affect the level of cellular insulin interfering with lipid metabolism, resulting in obesity among patients 26 .In this study, few individuals had increased weight within three months of follow-up.Our study revealed that most reported AEs were classified as disorders affecting skin and subcutaneous tissues, gastrointestinal system, nervous system, metabolism and nutrition, respiratory and thoracic system according to MedDRA.Similar findings were reported from Brazil, and Zambia 29,30 .Several other studies are also in tandem with our findings [31][32][33][34][35] .In our study, the overall incidence of occurrence of the first AE was 96.7 per 1000 person-months.This incidence rate is higher compared to 20-60 per 1000 person-months of ADRs among DTG users reported in previous studies [36][37][38][39][40] .However, our finding is lower than other studies conducted in South Africa and Congo 26,41,42 .The higher incidence observed in other studies might be due to longer follow-up times as compared to the present study.Furthermore, our study reports a lower median time for the first ADR (87.9 days) than a study in Brazil, which had a median time of occurrence of 210.6 days 25 .
The incidence rates of AEs were high in elderly participants aged 60 years and above and those who had a baseline WHO HIV clinical stage 2. The observed wide confidence intervals in the analysis may be explained by the few number of events observed.Nevertheless, this finding should be interpreted with caution as it may suggest little knowledge of the effect requiring further research.On further analysis, individuals on WHO HIV clinical stage 2 at baseline had significantly 2.7 higher AEs reported than those on stage 1.This finding is consistent with the findings from studies done in Brazil and Ethiopia 25,29,30 .Contrary to our finding, a study from Uganda reported that individuals who have initiated DTG-based regimens on lower stages 1, 2 and 3 were more likely to report AEs than those in stage 4. Individuals with advanced AIDS disease and elders may be more immunecompromised than those on stage 1, and younger, therefore, susceptible to developing AEs.
Our study had some limitations, which included a short period of follow-up which was 90 days.This might cause an underestimation of the actual effects of the DTG-based regimen.Nevertheless, our findings were similar to other studies with both longer and shorter follow-up times [36][37][38][39][40]43 , suggesting that the safety profiles of DTGbased regimens may not differ significantly with different times of follow-up. Onthe flip side, the strength of our study is the prospective design whereby AEs were reported as they occurred in real-world situations as well as involving many (n = 25) CTCs in 11 regions of the country.www.nature.com/scientificreports/ We recommend continued monitoring of the safety of the DTG-based regimen in the population, particularly in elders and those with advanced HIV disease.Further studies should focus on the long-term effects of DTG on the liver, kidney and other systemic organs.

Ethical statement
Ethical clearance was obtained from the National Institute for Medical Research (BA.126/329/01A/85) and the study was performed according to relevant regulations and guidelines.Permission to conduct the study was    www.nature.com/scientificreports/obtained from the relevant region, districts and health facility authorities.Written informed consent and assent were obtained from all eligible participants.All data were encoded and treated confidentially, following data security principles and good clinical practices.

Study design, population and setting
This was a prospective cohort study which involved PLHIV who were initiated on DTG based-regimen.The study included DTG naïve patients (newly ART initiated as well as clients who transitioned from another ART regimen to DTG).This study included individuals aged 12 years and above, newly diagnosed with HIV/AIDS and those initiated on or transitioned to Tenofovir, Lamivudine and Dolutegravir (TLD) during the study period.
The study excluded seriously ill and hospitalized individuals.The study was conducted in 25 Care and Treatment Clinics (CTCs) from 11 regions of Tanzania's mainland.The regions were purposefully selected to represent administrative zones of the country, namely; the eastern zone (Morogoro, Dar es Salaam and Pwani), northern zone (Arusha and Tanga), lake zone (Shinyanga, Geita and Mwanza), central zone (Dodoma) and southern highlands zone (Iringa and Songwe).The CTCs were purposively selected by considering the number of PLHIV who were about to be initiated/transitioned to a DTG-based regimen.The CTCs with a relatively large number of PLHIV who were about to be initiated/transitioned to DTG-based regimen in each region were purposefully included.The list of CTCs and the corresponding number of individuals recruited is shown in Table 4.

Data collection
Data were collected electronically using structured questionnaires through the Open Data Kit (ODK®).Prior to data collection, healthcare workers from selected CTCs were recruited as research assistants and were trained on essential components of the study, including a thorough orientation of the tools (i.e., informed consent/assent and study questionnaires).The tool was pre-tested in the field, validated and finalized.Baseline information collected were socio-demographic characteristics and clinical profiles of participants.The socio-demographic characteristics including sex, age, body weight, marital status and educational level were collected during recruitment; whereas clinical profile (WHO HIV clinical stage, presence of any comorbidities, CD4 cell count and treatment history) were abstracted from the client's medical records.The adverse events

Figure 2 .
Figure 2. Adverse events reported within 90 days following initiation of DTG based-regimen.

Figure 3 .
Figure 3. System Organ Classification (SOC) of the reported adverse events within 90 days following initiation of TLD.

Figure 4 .
Figure 4. Kaplan-Meier plot for the time to Adverse Events.

Table 1 .
Baseline characteristics of study participants.

Table 2 .
Incidence rate of occurrence of AEs across the population characteristics (N = 887).CI confidence interval.

Table 3 .
Predictors of incidence rates of reported AEs.cHR crude Hazard ratio, aHR adjusted Hazard ratio, CI confidence interval.Significant are in value [bold].

Table 4 .
List of health facilities and the number of recruited individuals.